PROJECT SUMMARY/ABSTRACT Advances in catalytic science and technology enable the preparation of pharmaceutical agents used to treat human disease. Catalytic cross coupling reactions are among the most commonly employed reac- tions for the assembly of drugs and drug candidates in the pharmaceutical industry. Aryl ethers and fluo- rides are common intermediates in synthesis, but they are still considered to be challenging electrophiles for catalytic cross coupling. Catalytic methods that open this class of electrophile to cross coupling and allow their selective functionalization would significantly aid in the preparation of bioactive small mole- cules. This exploratory research project has the goal of developing a new technology for strong bond ac- tivation that will enable broad advances in catalytic cross coupling reactions of recalcitrant substrates. The first major milestone will be to establish the stoichiometric activation of aryl C?O and C?F bonds across metal-ligand cooperative constructs and to realize catalytic cross coupling of these electrophiles. The second major milestone will be to achieve selective activation of C?O and C?F substrates in the presence of other functionalizable moieties. The proposed research is expected to yield new practical catalytic methods for the construction of pharmacologically-relevant small molecules that meet the chal- lenges of selective synthesis. Also, the research will establish a new technology for catalytic coupling based on the conceptualization of metal-ligand constructs as cooperative functional engines for bond making and breaking. Taken together, these outcomes will transform the practice of catalytic strong bond activation by the introduction of a new and powerful modality in homogeneous catalysis.